CN115124545B - Synthesis method of gonadotropin releasing hormone receptor antagonist intermediate - Google Patents
Synthesis method of gonadotropin releasing hormone receptor antagonist intermediate Download PDFInfo
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- CN115124545B CN115124545B CN202211062229.9A CN202211062229A CN115124545B CN 115124545 B CN115124545 B CN 115124545B CN 202211062229 A CN202211062229 A CN 202211062229A CN 115124545 B CN115124545 B CN 115124545B
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a new synthesis method of gonadotropin releasing hormone receptor (GnRH) antagonist intermediate 8-benzyl-3-oxo-1-oxa-8-aza [4,5] decane-4-carboxylic acid ethyl ester, belonging to the technical field of synthesis, and the specific synthesis method comprises the steps of adding a solvent into a compound shown in a formula (3) for dissolving, adding alkali into the compound shown in the formula (2), and reacting at a proper temperature to obtain a product shown in the formula (1); the preparation method disclosed by the invention has the advantages of few reaction steps, higher yield than that of the original reported literature, low cost, simple treatment after reaction and high product purity, and can fully meet the market demand.
Description
Technical Field
The invention belongs to the technical field of synthesis, and particularly relates to a novel synthesis method of gonadotropin-releasing hormone receptor (GnRH) antagonist intermediate 8-benzyl-3-oxo-1-oxa-8-aza [4,5] decane-4-carboxylic acid ethyl ester.
Background
The 8-benzyl-3-oxo-1-oxa-8-aza [4,5] decane-4-carboxylic acid ethyl ester has very important commercial value as an intermediate of gonadotropin releasing hormone receptor (GnRH) antagonist.
Among the synthetic methods that have been reported, the synthesis proceeds via the following synthetic route:
the process adopts two-step reaction to synthesize the target product, and sodium hydride is used in the two-step reaction, so that the yield is low.
Disclosure of Invention
The invention provides a new synthesis method of gonadotropin releasing hormone receptor (GnRH) antagonist intermediate 8-benzyl-3-oxo-1-oxa-8-aza [4,5] decane-4-carboxylic acid ethyl ester aiming at the defects in the prior art, and aims to solve the problems in the prior art.
In order to achieve the purpose, the technical scheme of the invention is as follows:
8-benzyl-3-oxo-1-oxa-8-aza [4,5] decane-4-carboxylic acid ethyl ester, the structural general formula is shown as the following formula (1):
a synthetic method of 8-benzyl-3-oxo-1-oxa-8-aza [4,5] decane-4-carboxylic acid ethyl ester comprises the following steps: the specific synthesis method comprises the steps of adding a solvent into the compound shown in the formula (3) for dissolving, then adding alkali into the compound shown in the formula (2), and reacting at 0-110 ℃ to obtain the product shown in the formula (1).
The reaction equation is as follows:
further, the molar ratio of the compound represented by the formula (3), the base, the compound represented by the formula (2), and the solvent is 1:1 to 5:1 to 2:5 to 50.
Further, the alkali is one or more of sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydride.
Further, when the alkali is sodium hydride, the synthesis method specifically comprises the following steps: adding a solvent into the compound shown in the formula (3) for dissolving, adding alkali, cooling to 0-10 ℃, adding the compound shown in the formula (2), and reacting at a proper temperature to obtain the product shown in the formula (1).
Further, the solvent is one or more of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide and toluene.
Further, when the solvent is tetrahydrofuran, the reaction temperature is 50-60 ℃.
Further, when the solvent is N, N-dimethylformamide or N, N-dimethylacetamide, the reaction temperature is 100-110 ℃.
Further, when the solvent is toluene, the reaction temperature is 80-90 ℃.
Further, the reaction time is 1-12 h.
Compared with the prior art, the invention has the beneficial effects that:
the invention belongs to the technical field of synthesis, and particularly relates to a novel synthesis method of 8-benzyl-3-oxo-1-oxa-8-aza [4.5] decane-4-carboxylic acid ethyl ester.
The synthesis method of the invention reduces the synthesis steps and improves the yield.
The preparation method disclosed by the invention is mild in reaction conditions, convenient to treat after reaction, high in product purity and capable of fully meeting market demands.
Drawings
FIG. 1 is a MS spectrum of a compound of formula (1) of example 5 of the present invention;
FIG. 2 shows example 5 of the present invention, a compound of formula (1) 1 H NMR spectrum;
FIG. 3 shows example 5 of the present invention for preparing a compound of formula (1) 13 C NMR spectrum.
Detailed Description
The present invention will be further illustrated with reference to the accompanying drawings and specific embodiments, which are to be understood as merely illustrative of the invention and not as limiting the scope of the invention.
Example 1:
10g of the compound of the formula (3) and 50g of tetrahydrofuran are added into a three-neck flask in sequence, stirred, added with 11.8g of potassium tert-butoxide and 14.4g of the compound of the formula (2), heated to 50-60 ℃ and reacted for 2h. After the reaction, the reaction solution was added to 100g of water, extracted three times with 100ml of ethyl acetate, the organic phase was concentrated to dryness under reduced pressure, and recrystallized with a solvent having a volume ratio of ethyl acetate to n-hexane of 1:6. 15.1g of a yellow solid are obtained in 90% yield and with an HPLC purity of 99.2344%.
Example 2:
10g of the compound of the formula (3) and 50g of tetrahydrofuran are added into a three-neck flask in sequence, stirred, added with 10.1g of sodium tert-butoxide and 14.4g of the compound of the formula (2), heated to 50-60 ℃ and reacted for 2h. After the reaction, the reaction solution was added to 100g of water, extracted three times with 100ml of ethyl acetate, the organic phase was concentrated to dryness under reduced pressure, and recrystallized with a solvent having a volume ratio of ethyl acetate to n-hexane of 1:6. 13.75g of a yellow solid are obtained in 82% yield and with an HPLC purity of 99.1342%.
Example 3:
adding 10g of the compound of the formula (3) and 50g of tetrahydrofuran into a three-neck flask in sequence, stirring, adding 2.75g of 60% sodium hydride, cooling to 0-10 ℃, dropwise adding 14.4g of the compound of the formula (2), stirring for 1h, slowly heating to 50-60 ℃, and reacting for 2h. After the reaction, the reaction solution was added to 100g of water, extracted three times with 100ml of ethyl acetate, the organic phase was concentrated to dryness under reduced pressure, and recrystallized with a solvent in which the volume ratio of ethyl acetate to n-hexane was 1:6. The yellow solid 14.76g was obtained in 88% yield and HPLC purity 97.1924%
Example 4:
a three-necked flask was charged with 10g of the compound of formula (3) and 50g of N, N-dimethylformamide in this order, stirred, charged with 11.8g of potassium tert-butoxide and 14.4g of the compound of formula (2), and heated to 100 to 110 ℃ to react for 2 hours. After the reaction, the reaction solution was added to 100g of water, extracted three times with 100ml of ethyl acetate, the organic phase was concentrated to dryness under reduced pressure, and recrystallized with a solvent having a volume ratio of ethyl acetate to n-hexane of 1:6. 14.2g of a yellow solid are obtained in 85% yield and with an HPLC purity of 98.2343%.
Example 5:
10g of the compound of the formula (3) and 50g of N, N-dimethylformamide were added to a three-necked flask in this order, followed by stirring, 10.1g of sodium t-butoxide and 14.4g of the compound of the formula (2) were added thereto, and the mixture was heated to 100 to 110 ℃ to react for 2 hours. After the reaction, the reaction solution was added to 100g of water, extracted three times with 100ml of ethyl acetate, the organic phase was concentrated to dryness under reduced pressure, and recrystallized with a solvent having a volume ratio of ethyl acetate to n-hexane of 1:6. 13.4g of a yellow solid are obtained in 80% yield and with an HPLC purity of 99.1041%.
MSm/z:{[M-H]-}316.73
1 H NMR (400 MHz, DMSO) δ = 7.48 – 6.99 (m, 5H), 3.98 (dd, J=22.2, 15.2, 4H), 3.59 (s, 6H), 2.66 – 2.50 (m, 2H), 2.27 (d, J=8.3, 3H), 1.24 – 0.98 (m, 3H).
13 C NMR (400 MHz, DMSO) δ 138.93, 129.33, 128.56, 127.27, 95.34, 83.88, 71.55, 62.62, 49.99, 40.57, 40.36, 40.15, 39.94, 39.74, 39.53, 39.32, 35.69, 15.16.
It should be noted that the above-mentioned contents only illustrate the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and it is obvious to those skilled in the art that several modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations fall within the protection scope of the claims of the present invention.
Claims (7)
1. A synthesis method of a gonadotropin releasing hormone receptor antagonist intermediate compound shown as a formula (1) is characterized in that the process route of the synthesis method is as follows:
the method specifically comprises the following steps: adding a solvent into the compound shown in the formula (3) for dissolving, adding alkali into the compound shown in the formula (2), and reacting at 0-110 ℃ to obtain a product shown in the formula (1);
the alkali is one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydride.
2. The method for synthesizing a gonadotropin-releasing hormone receptor antagonist intermediate compound shown as the formula (1) according to claim 1, wherein the molar ratio of the compound shown as the formula (3), the base, the compound shown as the formula (2) and the solvent is 1:1 to 5:1 to 2:5 to 50.
3. The method for synthesizing the gonadotropin-releasing hormone receptor antagonist intermediate compound shown in the formula (1) according to claim 2, wherein the solvent is one or more of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide and toluene.
4. The method for synthesizing the gonadotropin-releasing hormone receptor antagonist intermediate compound shown in the formula (1) according to claim 3, wherein the reaction temperature is 50-60 ℃ when the solvent is tetrahydrofuran.
5. The method for synthesizing the gonadotropin-releasing hormone receptor antagonist intermediate compound shown in the formula (1) according to claim 3, wherein when the solvent is N, N-dimethylformamide or N, N-dimethylacetamide, the reaction temperature is 100-110 ℃.
6. The method for synthesizing the gonadotropin-releasing hormone receptor antagonist intermediate compound shown in the formula (1) according to claim 3, wherein the reaction temperature is 80-90 ℃ when the solvent is toluene.
7. The method for synthesizing the gonadotropin-releasing hormone receptor antagonist intermediate compound shown in the formula (1) according to claim 1, is characterized in that the reaction time is 1-12 h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1033629A (en) * | 1987-10-05 | 1989-07-05 | 山之内制药株式会社 | Heterocyclic ring spiroring compounds and its preparation method |
| CN101007814A (en) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | Pyrrolehexa-heterocyclic compound and pharmaceutical use thereof |
| CN104136441A (en) * | 2012-02-28 | 2014-11-05 | Sk化学公司 | Gonadotropin releasing hormone receptor antagonists, method for the preparation thereof and pharmaceutical composition comprising the same |
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| WO2018026371A1 (en) * | 2016-08-04 | 2018-02-08 | Sunovion Pharmaceuticals Inc. | Dual nav1.2/5ht2a inhibitors for treating cns disorders |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1033629A (en) * | 1987-10-05 | 1989-07-05 | 山之内制药株式会社 | Heterocyclic ring spiroring compounds and its preparation method |
| CN101007814A (en) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | Pyrrolehexa-heterocyclic compound and pharmaceutical use thereof |
| CN104136441A (en) * | 2012-02-28 | 2014-11-05 | Sk化学公司 | Gonadotropin releasing hormone receptor antagonists, method for the preparation thereof and pharmaceutical composition comprising the same |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and polymerization of α-substituted fluoroacrylates. Part;J. M. Bessiere等;《Journal of Fluorine Chemistry》;19921231;第56卷(第3期);第295-303页 * |
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